Transferrin, in vitro inhibits fungal growth by restricting iron availability. Transferrin has not been shown to provide host defense in vivo. The objective of this grant is to establish if restricting iron availability provides host defense. Progress includes 1) Isolation of guinea pig transferrin and the production of an antiserum against it. This antiserum will be used in vivo to abrogate or inhibit the normal function of transferrin and in vitro in an immunoassay to quantitate guinea pig serum transferrin levels. 2) Methodology for defining and measuring the fungal quantitative iron requirement was developed. 3) Characterization of fungal surface iron chelating activity was begun. 4) The in vivo effect of injected iron on guinea pig transferrin was studied. Systemically pathogenic fungi were found to have a smaller iron requirement. The mechanism by which fungi acquire iron was determined to be a function of iron binding receptors located on the fungal surface. Rhizopus oryzae and T. mentagrophytes were extensively studied. The iron binding constants for these fungi and the number of receptor sites were similar. Iron binding by T. mentagrophytes was strongly cooperative, indicating initial binding significantly increases further iron binding. These data suggest that systemically invasive fungi have a selective advantage because of a diminished iron requirement and that fungi have receptors with significant avidity for iron. Iron receptor site function and fungal iron binding capacity may determine the potential for fungal growth in tissue where iron is abundant but not available. In vivo studies show that guinea pigs possess a compensatory mechanism to negate the introduction or release of excess iron in tissues. These studies support the hypothesis that the fungal capacity to acquire iron may play a significant role in the host-fungal-parasite interaction. This research may lead to new approaches of fungal therapy based upon the manipulation of iron availability.